The Molecular Imaging Branch (MIB) mainly aims to exploit positron emission tomography (PET) as a radiotracer imaging technique for investigating neuropsychiatric disorders, such as depression, schizophrenia and Alzheimer's disease. Fundamental to the mission of the MIB is the development of novel radiotracers that can be used with PET to deliver new and specific information on molecular entities and processes in the living animal or human brain (e.g. regional neuroreceptor concentrations, neurotransmitter synthesis, enzyme concentrations, regional metabolism, amyloid deposition, drug efflux from brain). PET is uniquely powerful for this purpose, provided that it can be coupled to appropriate radioactive probes (PET radiotracers). The chemical development of these probes is the key to exploiting the full potential of PET in neuropsychiatric research, but is also widely recognized as being a highly challenging and demanding scientific task.[unreadable] [unreadable] The PET Radiopharmaceutical Sciences Section of the MIB opened in August 2002 and now fulfills a pressing need for a concerted effort on PET radiotracer discovery (a process that has some parallels with drug discovery interms of required effort and risk). The laboratories are equipped and functioning with modern facilities for medicinal chemistry and automated radiochemistry with positron-emitting carbon-11 (t1/2 = 20 min) and fluorine-18 (t1/2 = 110 min). These short-lived radioisotopes are produced on a daily basis from the adjacent cyclotrons of the NIH Clinical Center in support of this research program.[unreadable] [unreadable] Our scientific program focuses on developing novel probes for imaging and quantifying a variety of brain receptors or proteins implicated in neuropsychiatric disorders e.g. cannabinoid (CB-1), serotonin (5-HT1A, 5-HT4), alpha-2, NET, PBR, and glutamate (mGluR5) receptors, and protein deposits such as beta-amyloid. Progress in some of these areas has been succesful, providing new radiotracers for CB-1, PBR and mGluR5 sites for brain imaging in human subjects in support of clinical research. This research is conducted under Food and Drug Administration oversight through 'exploratory' or full INDs. In reaching these significant goals, many candidate radiotracers were designed and prepared, and then some were found to give detectable specific signals in living animals with PET. Radiotracers developed for PBR appear highly successful and are destined to have broad application for the investigation of brain inflammatory conditions in response to neurological insults e.g., stroke and neurodegeneration. CB-1 receptors are the sites in the brain that are acted upon by cannabis. Our new CB-1 radiotracers have potential for the study of drug addiction, including alcoholism and cocaine addiction. These probes may also have relevance to the study of other disorders, such as obesity. Our mGluR radiotracer is expected to have value for the study of Fragile X syndrome, addiction and other disorders, such as schizophrenia. Such radiotracers have additional value in expediting drug discovery (see for example the recent popular feature article entitled 'A Chemical Map of The Mind - Targeted radiotracers help drug makers navigate the neurological landsacape by PET', published in Chemistry and Engineering News, Sep 8th, 2008, which discusses our mGluR radiotracer and other probes). The imaging of drug efflux pumps (e.g., P-gp) at the blood-brain barrier is a new area of interest in our laboratory with relevance to drug development for neuropsychiatric disorders. A much improved radiotracer, named C-11dLop, has been developed for this purpose, and has now reached the level of study in human subjects. This radiotracer has potential value for assessing the role of efflux pumps in disorders such as Alzheimer's disease and other neurodegenerative disorders (e.g., Parkinson's disease).[unreadable] [unreadable] Some of the developed radiotracers are also likely to have value foor diseases manifested outside the brain. Thus, the PBR radiotracers may be generic for the study of inflammation in the periphery (e.g., as occurs in atherosclerosis), and the P-gp radiotracer for the study of cancer (especially multi-drug resistance).[unreadable] [unreadable] All imaging studies are performed through close multi-disciplinary interaction with the Imaging Section of the Molecular Imaging Branch (Chief of Section and Branch, Dr. R.B. Innis, MD, PhD).[unreadable] [unreadable] Methodology underpinning our developments was also advanced in areas such as the development of new synthetic methods, new radiolabeling procedures, polymer-supported labeling reactions, microwave-enhanced chemistry and radiochemistry, and the application of micro-reactors to the miniaturization of radiochemistry. These advances are seen as being vital for expanding the scope for generating new radiotracers and for facilitating their applications. New analytical methods, based on for example liquid chromatography coupled to mass spectrometry, have also been developed and exploited to understand the biochemical fate of radiotracers in living systems - information which is needed to fully understand the results from PET experiments and to derive meaningful measures, such as brain receptor concentrations. [unreadable] [unreadable] Productive collaborations have been established with external academic chemistry and medicinal chemistry laboratories, nationally and internationally, and also with pharmaceutical companies through a series of CRADAs (Cooperative Research and Development Agreements). Productive collaborations also exist with other centers working with PET and its associated radiochemistry and radiotracer development. The laboratory is also active in training new scientists for this field at all levels.[unreadable] [unreadable] In addition we also produce several established radiotracers for PET investigations in animals e.g., F-18SPA-RQ (for NK1-receptor imaging), F-18Fallypride (for dopamine type), C-11Rolipram (for PDE4 enzyme imaging), C-11MNPA (for functional dopamine-2 receptor imaging)and C-11PK 11195 (PBR binding site imaging). The production of some of these radiotacers comply with FDA requirements under exploratory or full INDs and these radiotracers are available for brain imaging in human subjects under clinical research protocols. Each PET experiment with one of these radiotracers requires a radiosynthesis of the radiotracer on the same day, and hence radiotracer production is a regular activity.